1. Field of the Invention
The present invention relates generally to the fields of pharmacogenetics and cancer therapy. More particularly, it concerns methods and compositions for predicting or anticipating the level of toxicity of irinotecan and other compounds glucuronidated by a UGT enzyme in a patient. Such methods and compositions can be used to evaluate whether irinotecan-based therapy or therapy involving a UGT substrate may pose toxicity problems if given to a particular patient. Alterations in suggested therapy may ensue if toxicity may pose a problem.
2. Description of Related Art
Irinotecan is a topoisomerase I inhibitor that is approved worldwide for the treatment of metastatic colorectal cancer. Irinotecan has a well established role as single agent in 5-fluorouracil-refractory patients (Rougier et al., 1998; Cunningham et al., 1998), as well as in combination with 5-fluorouracil/leucovorin as a first-line therapy (Saltz et al., 2000; Rothenberg et al., 2001). Its role in the adjuvant setting is being explored.
Despite its efficacy in this disease and its broad spectrum of activity in other tumor types, irinotecan treatment is associated with significant toxicity. The main severe toxicities of irinotecan are delayed diarrhea and myelosuppression. In the early single agent trials, grade 3-4 diarrhea occurred in about one third of patients and was dose limiting (Negoro et al., 1991; Rothenberg et al., 1993). Its frequency varies from study to study and is also schedule dependent. The frequency of grade 3-4 diarrhea in the three-weekly regimen (19%) is significantly lower compared to the weekly schedule (36%, Fuchs et al., 2003). In addition to diarrhea, grade 3-4 neutropenia is also a common adverse event, with about 30-40% of the patients experiencing it in both weekly and three-weekly regimens (Fuchs et al., 2003; Vanhoefer et al., 2001). Fatal events during irinotecan treatment have been reported. A high mortality rate of 5.3 and 1.6% was reported in the weekly and three-weekly single agent irinotecan regimens, respectively (Fuchs et al., 2003).
While some information may be known about how to predict the patients who will eventually suffer intolerable toxicities (Ratain, 2002), additional information can be useful. Although this scenario seems discouraging, the risk of severe toxicity might be predicted by understanding the pharmacology of irinotecan and investigating the genetic variation of irinotecan metabolism. Irinotecan hydrolysis by carboxylesterase-2 is responsible for its activation to SN-38 (7-ethyl-10-hydroxycamptothecin), a topoisomerase I inhibitor of much higher potency than irinotecan (ref). The main inactivating pathway of irinotecan is the biotransformation of active SN-38 into inactive SN-38 glucuronide (SN-38G). Interpatient differences in systemic formation of SN-38G have been shown to have clear clinical consequences in patients treated with irinotecan. Patients with higher glucuronidation of SN-38 are more likely to be protected from the dose limiting toxicity of diarrhea in the weekly schedule (Gupta et al., 1994). SN-38 is glucuronidated by UDP-glucuronosyltransferase 1A1 (UGT1A1) (Iyer et al., 1997)
The UGT1A1 genetic variation has been extensively investigated in relation to hyperbilirubinemic syndromes, as UGT1A1 enzyme catalyzes the glucuronidation of bilirubin (ref). A variable number of repeats (5, 6, 7, and 8) have been found in the UGT1A1 TATA box. Gene transcriptional efficiency has been inversely correlated to the number of TA repeats (Beutler et al., 1998). Homozygosity for the (TA)7 allele has been associated with the classical picture of Gilbert's syndrome, a common mild hyperbilirubinemia (Burchell et al.; Monaghan et al.). Gilbert's syndrome has also been associated with missense coding variants in the UGT1A1 gene, in particular in Asian populations where these variants are relatively common.
Because of the clinical importance of the glucuronidation pathway in irinotecan treatment, UGT1A1 is the candidate gene to be investigated in order to predict the events of severe toxicity after irinotecan treatment. Although retrospective analysis of UGT1A1 genetic variation in relation to severe toxicity after different irinotecan-based regimens has been conducted in Japanese patients (Ando et al., 2000), prospective evaluation in a large trial has not been performed.